Red blood cell destruction in autoimmune hemolytic anemia: role of complement and potential new targets for therapy

Abstract

Autoimmune hemolytic anemia (AIHA) is a collective term for several diseases characterized by autoantibody-initiated destruction of red blood cells (RBCs). Exact subclassification is essential. We provide a review of the respective types of AIHA with emphasis on mechanisms of RBC destruction, focusing in particular on complement involvement. Complement activation plays a definitive but limited role in warm-antibody AIHA (w-AIHA), whereas primary cold agglutinin disease (CAD), secondary cold agglutinin syndrome (CAS), and paroxysmal cold hemoglobinuria (PCH) are entirely complement-dependent disorders. The details of complement involvement differ among these subtypes. The theoretical background for therapeutic complement inhibition in selected patients is very strong in CAD, CAS, and PCH but more limited in w-AIHA. The optimal target complement component for inhibition is assumed to be important and highly dependent on the type of AIHA. Complement modulation is currently not an evidence-based therapy modality in any AIHA, but a number of experimental and preclinical studies are in progress and a few clinical observations have been reported. Clinical studies of new complement inhibitors are probably not far ahead.

Figure 1

The complement cascade, simplified. Only components relevant for this paper are shown. The lectin and alternative pathways, converging with the classical pathway at the C3 activation level, are indicated but not shown in detail. Physiological inhibitors and positive feedback loops are not shown. C: complement protein; MAC: membrane attack complex.

Figure 2

Mechanisms of erythrocyte destruction in warm-antibody autoimmune hemolytic anemia. Ig: immunoglobulin; C: complement protein.

Figure 3

Immune-initiated, complement-mediated erythrocyte destruction in cold agglutinin disease (CAD) and cold agglutinin syndrome (CAS). See text for further explanation. Black arrows: major pathway; gray/dotted arrows: minor pathway; CA: cold agglutinin; C: complement protein.

Figure 4

Immune-initiated, complement-mediated erythrocyte destruction in paroxysmal cold hemoglobinuria (PCH) showing a biphasic temperature optimum. Black arrows: major pathway (intravascular hemolysis); gray/dotted arrows: possible minor pathway; Ig: immunoglobulin; ag: antigen; ab: antibody; C: complement protein.

Figure 5

In vitro effects of anti-C1s antibody TNT003 on phagocytosis (black columns, left y-axis) and complement fragment deposition (red columns, right y-axis) on red blood cells after addition of normal human plasma and cold agglutinin-rich plasma (under blue bar), respectively. TNT003 inhibits phagocytosis and complement deposition, while anti-C5 has no impact. CAD: primary chronic cold agglutinin disease; NHS: normal human serum; IC: isotype control. Reproduced from Blood (Shi et al. 2014, [10]) with permission. Copyright: Blood, the Journal of the American Society of Hematology.

Figure 6

Future perspective on complement modulation in AIHA. Inhibitors and levels of inhibition. Black arrows: major pathway in cold agglutinin disease (CAD); gray/dotted arrows: minor pathway in CAD and major pathway in paroxysmal cold hemoglobinuria; Ig: immunoglobulin; C: complement protein; TNT003: mouse monoclonal C1s antibody; C1-INH: C1 esterase inhibitor. Previously published in Blood (Berentsen 2014, [11]), reused with permission. Copyright: Blood, the Journal of the American Society of Hematology.